The overall aim of this project is to examine the role of the virus-receptor interaction in the pathogenesis of AIDS. The project will build upon our earlier work demonstrating that CXCR-4 and CD134 are the major co-receptor and primary binding receptor respectively for feline immunodeficiency virus (FIV), the lentivirus of the domestic cat. In the cat, FIV infection induces an immunodeficiency syndrome similar to AIDS in HIV-infected humans. In the proposed studies, we will ask whether receptor usage is a major determinant of FIV pathogenicity and whether viruses with distinct receptor usages are present during early and late infection. In the previous funding period, we showed that primary strains of FIV require the co-expression of CD134 in addition to CXCR-4 in order to infect target cells. Aim 1 of this competing renewal will ask whether CD134-usage is ubiquitous amongst diverse isolates of FIV, examining the receptor usage of viruses from distinct geographical origins and genetic backgrounds. Aim 2 will focus on the interaction between the viral envelope glycoprotein (Env) and CD134, mapping the viral binding site and asking whether Env binding perturbs the normal cellular function of CD134 in the expansion and survival of antigen-specific T cells. This section will address how the Env-CD134 interaction contributes to the pathogenesis of AIDS in the cat, of great significance to the interpretation of studies using FIV as an animal model for AIDS. Finally, in Aim 3 we will investigate whether viruses with distinct biological phenotypes exist in early and late infection. Preliminary observations suggest that viruses derived from asymptomatic cats have distinct cell tropisms, receptor usages and biological properties in vivo compared to those derived from symptomatic cats. Moreover, as they achieve higher viral loads in vivo, and predominate in early infection, it is likely that these isolates are the ones that are transmitted in the field. As the majority of isolates studied to date have been derived from animals displaying clinical signs of infection, these studies are of profound importance to the selection of viruses for future trials of novel vaccines and therapeutics in this widely used small animal model of AIDS.